Process for the preparation of 5-nitroimidazole-2-carboxylic acids



United States Patent 3,325,507 PROCESS FOR THE PREPARATION OF S-NITRO-IMIDAZOLE-Z-CARBQXYLIC ACIDS Janos Kollonitsch, Westfield, NJ, assignorto Merck & Co., Inc, Rahway, Ni, a corporation of New Jersey No Drawing.Filed Nov. 27, 1963, Ser. No. 326,392 3 Claims. (Cl. 260-309) Thisinvention relates generally to the synthesis of imidazole-carboxylicacids. More particularly, it relates to the preparation of l-loweralkyl-S-nitroimidazole-Z-car- 'boxylic acids. Still more specifically,it is concerned with a new and novel method of obtaining l-loweralkyl-S- nitroimidazole-2-carboxylic acids from the correspondingZ-hydroxyrnethyl imidazoles.

l-lower alkyl-S-nitroimidazole-2-carboxylic acids are importantcompounds for the preparation of l-lower alkyl-S-nitroimidazole-2-carboxamides, which latter substances have a veryhigh degree of activity against the parasitic diseases histomoniasis andT. vaginalis vaginitis. These imidazole-Z-carboxylic acids are highlyunstable compounds under many conditions. Heretofore, they have beenprepared in alkaline media and isolated in the form of alkali metalsalts in order to avoid or minimize decarboxylation of the free acid.One method of producing such carboxylic acids is by oxidation of a1lower alkyl-Z- hydroxymethyl-5-nitroimidazoles, as shown structurallybelow:

where R represents lower alkyl and Y is hydrogen or an alkali metal.Previous work has been limited to the use of alkaline oxidizing agentswhich lead to formation of salts. These methods are not feasible on apractical basis, and the yields thus obtained are not satisfactory. Manyacidic oxidizing systems afforded no improvement due to destruction ofthe imidazole ring or spontaneous decarboxylation of the imidazolecarboxylic acid.

In accordance with the present invention, it has now been found thatl-lower alkyl-S-nitroimidazole-2-carboxylic acid is surprisingly stableunder certain strongly acidic conditions and that the free acid can infact be prepared in high yield by the oxidation under such acidicconditions of l-lower alkyl-Z-hydroxymethyl-S-nitroimidazole. It istherefore an object of this invention to provide a new synthesis ofl-lower alkyl-S-nitroimidazole-Z-carboxylic acid. It is a further objectto provide a synthesis which affords the free carboxylic acid in highyield. A still further object is provision of a synthesis in which theundesired oxidation of the imi-dazole ring and decarboxylation of thefree acid is essentially eliminated. Further objects will become clearfrom the following description of the invention.

It has now been found that l-lower alkyl-S-nitroimidazole-Z-carboxylicacids (Formula II above, where Y is hydrogen) are produced in high yieldon treatment of the corresponding Z-hydroxymethyl imidazole with anacidic oxidizing agent in a sulfuric acid medium. As the oxidant, theremay be used oxidizing agents such as nitric acid, nitrogen tetroxide,chromic acid (i.e. chromium trioxide) or manganese dioxide. Thepreferred oxidizing agent is nitric acid. The amount of oxidant employedis not critical to the success of this process, although it is desirableto employ at least an equimolar quantity with respect to thenitroimidazole reactant. For best results, the oxidizing agent should bepresent in excess, and I prefer to use from about 1-3 moles of oxidizingagent per mole of l-lower alkyl-Z-hydroxymethyl- 5-nitroimidazole.

A key feature of my invention is the carrying out of the oxidation in asulfuric acid medium. The reaction medium does not have to be anhydrous,but it should not contain more than about 25% by weight of water sincethe yield of l-lower alky-l-5-nitroimidazole-2-carboxylic acid isreduced considerably when more water is present. This loss of yield isapparently due to decarboxylation of the free acid. It is thereforepreferred to keep the amount of water in the reaction medium to aminimum. Concentrated sulfuric acid is preferably employed as thesolvent, although fuming sulfuric acid can be used if desired. Somewater will, of course, be introduced with certain oxidizing agents, suchas concentrated nitric acid, but this does not adversely affect theprocess as long as the total amount of water in the final medium is lessthan about 25% by weight.

The amount of sulfuric acid used as reaction solvent is not undulycritical except that sufficient should be present to dissolve thel-lower alkyl-Z-hydroxymethyl-S- nitroimid azole reactant and to providea reaction mixture that is sufiiciently fluid to permit stirring oragitation during the course of the process. Generally good results areachieved by employing from about 3-10 moles of concentrated sulfuricacid per mole of l-lower alkyl-2- hydroxymethyl-S-nitroimidazole.

The oxidation is conducted at elevated temperatures of at least aboutC., and preferably at 70-90 C. 'Even at these temperatures, the processis not a rapid one, and reaction times of at least about 10 hours arenormally employed. For best results at temperatures of 7'090 C., it ispreferred to continue the reaction for at least 15 hours; however,periods of up to 70 hours may be used without adverse effect.

At the end of the oxidation, the l-loweralkyl-5-nitroimidazole-Z-carboxylic acid may be isolated by quenchingthe highly acidic reaction mixture in ice or ice-water. Thewater-insoluble free acid, which is reasonably stable in the cold,precipitates and is recovered by filtration or centrifugation.

Employing the acidic oxidant-sulfuric acid system of this invention,there may be obtained l-lower alkyl-S- nitr-oimidazole-Z-carboxylicacids, examples of which are the 1-methyl, l-ethyl, l-propyl andl-butyl-5-nitroimidazole-2-carboxylic acid, from the correspondingl-lower alkyl-Z-hydroxymethyl-S-nitrioimidazole. These acids may beconverted to the corresponding antiparasitic amides via a lower alkylester, such as the methyl ester. If desired, such ester can be formeddirectly, without isolation of the free acid, by addition of methanol tothe sulfuric acid reaction medium after removal of excess oxidizingagent. The methyl ester of l-lower alkyl-S-nitroimidazole-Z- carboxylicacid is then precipitated on dilution of the sulfuric acid solution withWater. The amide is obtained on treatment of the ester with ammonia.

The following examples are given for the purpose of illustration and notby way of limitation.

Example 1 4.71 g. (0.03 M) of 1-methyl-2-hydroxymethyl5-nitroimidazoleis added with stirring to 16.5 g. (0.17 M) of concentrated sulfuricacid. 6.66 g. of nitric acid (0.072 M) is then added to the sulfuricacid mixture. The resulting solution is heated for 60 hours at -80" C.At the end of this time the reaction mixture is added slowly to 30 g. ofice. l-methyl-5-nitroimidazole-2-carboxylic acid precipitates and isrecovered by filtration. It is Washed with water and dried in vacuo atroom temperature. 3.5 g. of product are obtained, M.P. 8485 C.

a (dec.) The mother liquor is adjusted to pH 2 with sodium bicarbonate,whereupon an additional 0.7 g. of l-methyl-S-nitroimidazole-Z-ca1'boxylic acid precipitates.

Similar results are obtained when the above process is carried out byheating at 7580 C. for 15 hours instead of 60 hours.

' Example 2 The l-lower alkyl-S-nitroimidazole-2-carboxylic acidsobtained by the method of this invention are converted to thecorresponding imidazole-2-carboxamides as follows:

13.7 g. of 1-methyl-5-nitroimidazole-Z-carboxylic acid is suspended in10 ml. of ice water in an ice bath. 57 ml. of 2.5 N sodium hydroxide isadded in small portions with cooling and stirring. The resultingsolution is poured into 800 ml. of isopropanol and the mixture cooled inan ice bath. Sodium 1-methyl-5-nitroimidazole-2-carboxylateprecipitates, and is recovered by filtration.

9.70 g. of sodium 1-methyl-5nitroimidazole-2-carboxylate is suspended inbenzene. 30 ml. of oxalyl chloride is added and the reaction mixtureallowed to stand until the evolution of gas subsides. It is then warmedto reflux on a steam bath, then the benzene is evaporated in vacuo. Theresulting crude solids are flushed with benzene to remove any traces ofoxalyl chloride. The solid lmethyl- 5-nitroimidazole-2-carbonyl chloridewhich remains is extracted with warm benzene. The benzene extract isfiltered to remove any solid, and concentrated to dryness in vacuo. The1-methyl-S-nitr0i-midazole-2-carbonyl chloride crystallizes, M.P.150-l53 C.

0.86 g. of 1-methyl-5-nitroimidazole-2-carbonyl chloride is suspended in5 ml. of benzene. The resulting suspension is filtered to removeinorganic salts. An excess of anhydrous ammonia is bubbled into thebenzene solution, with rapid stirring. The benzene is then removed invacuo, and the residue of 1-methyl-S-nitroimidazole-Z-carboxamide isdissolved in a minimum amount of ethyl acetate. The ethyl acetatesolution is filtered and the filtrate concentrated to dryness. Theresidual l-methyl-S-nitroimidazole-2-carboxamide is recrystallized fromacetone to give substantially pure material, M.'P. 222-224 C. (subl).

This conversion of the carboxylic acids of this invention to theimidazole-2-carboxarnides is not a part of the present invention but israther the invention of my colleague Dale R. Hoff, and is subject matterof his application No. 300,629, filed Aug. 7, 1963. Such l-lower alkyl-5 -nitroimidazole-2-carboxamides are useful in treating turkeyblackhea-d disease, and for this purpose are orally administered toturkeys via the feed or drinking water of the birds.

Example 4 The l-lower alkyl-Z-hydroxymethyl-S-nitroimidazoles employedas starting materials for this invention are obtained by the procedureexemplified below for making the l-methyl compound:

27.9 g. of 1-methyl-5-nitroimidazole and 30.1 g. of para formaldehydeare added to 154 ml. of dirnethylsulfoxide and the resulting solution issealed into a glass-lined tube. The solution is then removed from thereaction vessel and the dimethylsulfoxide removed by distillation at 53-56 C./2 mm. The residue is extracted with 3x150 ml. of hot benzene. Thebenzene extracts are combinedand cooled to room temperature.1-methy1-2-hydroxymethyl- S-nitroimidazole crystallizes, and isrecovered by filtration. 23 g. of product are obtained, M.P. 112114.5 C.

When this procedure is followed using 31 g. of 1-ethyl- S-nitroimidazoleas starting material, 1-ethyl-2-hydroxymethyl-S-nitroimidazole isobtained.

This direct formylation method is not the subject of the presentapplication, but is rather the invention of my co-pending applicationNo. 326,379, filed Nov. 27, 1963, now abandoned.

Any departure from the above description which conforms to the presentinvention is intended to be included within the scope of the claims.

What is claimed is:

1. The process for preparing l-lower alkyl-S-nitroimidazole-2-carboxylicacid that comprises treating a compound of the formula where Rrepresents lower alkyl, with nitric acid in a sulfuric acid reactionmedium containing less than about 25 weight percent of water at atemperature of between 60 C. and C.

2. The process for preparing 1-methyl-5-nitroimidazole- Z-carboxylicacid that comprises treating 1-methyl-2-hydroxymethyl-S-nitroimidazolewith nitric acid in a sulfuric acid reaction medium containing less thanabout 25 weight perccglt of water at a temperature of between 60 and 903. The process for preparing 1-rnethyl-S-nitroimidazole- Z-carboxylicacid that comprises treating 1-rnethyl-2-hydroxymethyl-S-nitroirnidazolewith nitric acid in concentrated sulfuric acid at a temperature ofbetween 60 and 90 C.

References Cited UNITED STATES PATENTS 1,576,999 3/1926 Seydel 260-6872,475,969 7/1949 Larrison 260687 2,673,216 3/1954 Goedkoop 260-6872,694,070 11/1954 Martin 260-687 2,794,813 6/ 1957 Farinacci 260-687WALTER A. MODANCE, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

NATALIE TROUSOF, Assistant Examiner.

1. THE PROCESS FOR PREPARING 1-LOWER ALKYL-5-NITROIMIDAZOLE 2-CARBOXYLICACID THAT COMPRISES TREATING A COMPOUND OF THE FORMULA